PROJECT SUMMARY Physical inactivity is known to contribute to a broad array of health problems throughout the lifespan, but biomechanical factors that limit physical activity are poorly understood. The skeleton is known to adapt to its activity-dependent loading, and skeletal structure is especially plastic during growth. Studies of animal models have revealed differences in bone shape and joint structure between groups that are physically inactive and active during growth, but the post-growth consequences of these changes have not yet been examined. Preliminary experiments (N = 30) with a bipedal animal model (the guinea fowl Numida meleagris) have revealed differences between inactive and active animals that musculoskeletal computer models predict will compromise torque- and power-generating capacity in animals raised in inactivity. This diminished function may reduce locomotor performance and increase effort when inactive animals with suboptimal musculoskeletal structure struggle to move in an optimal fashion. The purpose of the work proposed in this R21 application is to determine the effects of growth-period inactivity upon not only musculoskeletal structure but also locomotor performance, both immediately post-growth and after a period of adult inactivity. This goal will be addressed using a rigorous approach that combines: (1) an experimental design in which guinea fowl are subjected to normal activity, general inactivity, and disuse that is focused upon a single muscle group and a single joint using botulinum toxin A, a neuromuscular blocking agent; and (2) musculoskeletal computer modeling to identify links between altered structure and reduced function. We will assess musculoskeletal structure and locomotor function immediately following growth (at 26 wks) and we will determine whether differences found after growth persist into an inactive adulthood (at 52 wks). If successful, this work will lead to better understanding of the consequences of inactivity during growth on locomotor function and will lead to novel interventions designed to minimize biomechanical barriers to activity and thus enhance lifelong health and mobility.